REVERSAL OF THE SEDATIVE AND SYMPATHOLYTIC EFFECTS OF DEXMEDETOMIDINEWITH A SPECIFIC ALPHA(2)-ADRENOCEPTOR ANTAGONIST ATIPAMEZOLE - A PHARMACODYNAMIC AND KINETIC-STUDY IN HEALTHY-VOLUNTEERS

Background Specific and selective alpha(2)-adrenergic drugs are widely exploited in veterinary anesthesiology. Because alpha(2)-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with atipamezole, an al pha(2)-antagonist, in healthy persons. Methods: The study consisted of two parts. In an open dose-finding study (part 1), the intravenous do se of atipamezole to reverse the sedative effects of 2.5 mu g/kg of de xmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of atipamezole (15, 50, and 150 mu g/kg given intrav enously in 2 min) or saline were administered 1 h after dexmedetomidin e at 1-week intervals (n = 8), Subjective vigilance and anxiety, psych omotor performance, hemodynamics, and saliva secretion were determined , and plasma catecholamines and serum drug concentrations were measure d for 7 h. Results: The mean +/- SD atipamezole dose needed in part 1 was 104 +/- 44 mu g/kg. In part 2, dexmedetomidine induced clear impai rments of vigilance and psychomotor performance that were dose depende ntly reversed by atipamezole (P < 0.001). Complete resolution of sedat ion was evident after the highest (150 mu g/kg) dose, and the degree o f vigilance remained high for 7 h. Atipamezole dose dependently revers ed the reductions in blood pressure (P < 0.001) and heart rate (P = 0. 009). Changes in saliva secretion and plasma catecholamines were simil arly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after atipamezole). Plasma norepinephrine l evels were, however, increased considerably after the 150 mu g/kg dose of atipamezole. The pharmacokinetics of atipamezole were Linear, and elimination half-lives for both drugs were approximately 2 h. Atipamez ole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approx imately 3 h after receiving dexmedetomidine. Conclusions: The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous atipamezole. The applied infusi on rate (75 mu g . kg(-1) . min(-1)) for the highest atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Si milar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.